Patent EP-0140709-A2 (EP)
Inventor: ATKINSON JOSEPH G
IPC: A61K31/495
Filed: 1984-10-30
Abstract: Compounds of the Formula I:
     and their pharmaceutically acceptable salts are inhibitors of the mammalian 5-lipoxygenase enzyme system of the arachidonic acid cascade. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation and are incorporated into pharmaceutical compositions. Certain of the compounds are novel. 
     In the formula,
     Z is O, NCN, SO or SO 2 ;   R, is H, C 1-6  alkyl, benzyl, C 1-6  acyl, C 1-6  aminoacyl, (C 1-6  alkylacyloxy)-(C 1-6  alkyl), (C 1-6  alkoxy)-(C 1-6  alkyl), -(CH 2 ) n  COOR 6  where n is, 0, 1, 2, 3 or 4, CN, (C 1-6  alkyl)acyloxy-(C 1-6  alkoxy)carbonyl, -C(R 7 ) = C(R 7 )COOR 6  or SO 2 R 10 ;   each of R 2 , R 3 , R 4  and R 5 , independently of the others, is hydrogen, C 1-6  alkyl, C 2-6  alkenyl or -(CH 2 ) n M, where n is 0 or an integer from 1 to 6 and   M is(a) OR 16 
   (b) halogen;   (c) CF 3 .   (d) SR 16 ;   (e) phenyl;   (f) substituted phenyl where the substituents(s) is/are C 1-3  alkyl, halogen, CN, C 1-3  alkoxy, OH, (CH 2 ) n NR 8 R 9  where n is 0, 1 or 2, CF 3 , COOR 6  or CH 2 COOR 6 ; (herein called «substituted phenyl as defined»);   (g) COOR 6 ;   (h) -CO-R 14 ;   (i) tetrazolyl;   (j) NH-CO-R 7 ;   (k) NR 8 R 9 ;   (I) NHSO 2 R 10 ;   (m) -CO-CH 2 0H;   (n) SOR 11  where R 11  is C 1-6  alkyl, phenyl, substituted phenyl as defined, (CH 2 ) m COOR 6 , where m is an integer from 1 to 6, or CF 3 ;   (o) CONR 8 R 9 ;   (p) SO 2 NR 8 R 9 ;   (q) S0 2 R 13  where R 13  is OH, C 1-6  alkyl, H phenyl, substituted phenyl as defined, (CH 2 ) m COOR 6  or CF 3 ;   (r) N0 2 ;   (s) -OCO-R 14 ;   (t) -OCO-NR 8 R 9 ;   (u)-OCO-OR 7 ; or   (v) -CN;       each R 16 , independently of any other, is H; (C 1-6  alkoxy)-(C 1-6  alkyl); (C 1-6  alkyl)acyloxy(C 1-6  alkyl); C 1-6  alkyl; substituted phenyl as defined; -CH 2 ) m COOR 6 ; CN: C 1-5  alkylacyl; C 1-4  perfluoroalkyl; phenyl; benzyl; or CH 2 -R 12  where R 12  is C 1-5  alkyldimethylamino;   each R 6 , independently of any other, is H, C 1-6  alkyl, benzyl or phenyl;   each R 14 , independently of any other, is H, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkyl)acyloxy(C 1-6  alkoxy), (CH 2 ) n COOR 6  where n is 0 or an integer from 1 to 4, phenyl or substituted phenyl as defined or is such that R 14 COOH is an essential amino acid;   each of R 8  and R 9 , independently of the others, is H, phenyl, substituted phenyl as defined or C 1-4  alkyl, or NR 8 R 9  is a heterocycloalkyl of 5 to 8 ring atoms; and   each R 7 , independently of the others, is H, C 1-6  alkyl, benzyl, phenyl or (C 1-6  alkyl)acyloxy-(C 1-6  alkoxy);   each R 10  is independently OH, C 1-6  alkyl, C 1-6  alkoxy, phenyl or p-tolyl;   or any two of R,, R 2 , R 3 , R 4  or R 5  are joined to form an additional ring of 5 to 7 members that optionally contains a carbonyl group and/or a hydroxyl group as substituent(s), and that has 0, 1 or 2 double bonds, and such that, if R, is a constituent of the ring, one member is nitrogen and the others are carbon and if R 1  is not a constituent of the ring, all the members are carbon; and   T is hydrogen or OR 15  where R 15  is hydrogen, C 1-6  alkyl, C 1-6  alkylacyl, phenyl-(C 1-8  alkyl)acyl, SO 2 R 10 , arylsulfonyl, -CO-phenyl or substituted phenyl as defined.